The present invention is directed to the identification and use of ribonucleoside analogs to induce the mutation of an RNA virus, including HIV and HCV, or a virus which otherwise replicates through an RNA intermediate.
RNA viral diseases are responsible for the vast majority of viral morbidity and mortality of viral diseases of mankind, including AIDS, hepatitis, rhinovirus infections of the respiratory tract, flu, measles, polio and others.
Acquired Immune Deficiency Syndrome (“AIDS”) is a fatal human disease that has recently grown in epidemic proportions. Current estimate is that there are approximately one million surviving infected individuals in the United States and tens of millions throughout the world. Epidemiological evidence indicates that this disease is caused by the human immunodeficiency viruses, HIV-1 or HIV-2.
HIV is particularly difficult to eradicate for several reasons, including that it permanently incorporates its genetic material into the genome of infected cells, it replicates (Perelson, A. S., Science 271:1582 (1996) and mutates (Larder, B. A., Science 246:1155 (1989) at an exceptionally high rate and thereby avoids immune inactivation, and it specifically infects and destroys the very immune system components most critical to controlling the infection. There is currently no effective vaccine for prevention of infection, and aside from the recent preliminary success for combination therapies involving protease inhibitors, few treatments of this fatal disease. Furthermore, the virus rapidly develops mutations conferring resistance against all chemotherapeutic agents tested to date.
All currently approved anti-AIDS drugs are designed to inhibit either the human immunodeficiency virus reverse transcriptase (HIV RT) or the virally encoded protease or a combination thereof. Chemicals directed against HIV RT are either deoxynucleoside analogs that terminate HIV DNA synthesis or non-nucleoside analogs that inhibit the reverse transcriptase (Larder, B. A., J. Gen. Virol. 75:951 (1994). The guiding concept of all current AIDS therapies is to prevent the further replication of the virus by directing drugs to interfere with the production or maturation of viral encoded proteins. Unfortunately, the therapeutic effectiveness of these drugs is generally rendered obsolete by the emergence of viral resistance. It has been estimated that the mutation rate of HIV is one million times greater than the mutation rate of human cells, leading to substantial genetic heterogeneity. Recently, combinations of drugs have been shown to be more effective in reducing the viral load in individuals and it is hoped that this reduction in viral load will result in prolongation of life (Ho, D., Science 272:1125 (1996). It remains to be determined whether or not the reduction in circulating virus will prevent the development of drug resistant mutants in an infected individual. Furthermore, the rigors of the current treatment modalities that slow or prevent the appearance of protease inhibitor (PRI) resistant virus are so extreme that it is unlikely that they will be consistently adhered to, hence the spread of PRI resistant virus is expected to occur and increase over time, sharply curtailing expectations of drug efficacy. Moreover, the high mutation rate of HIV guarantees that while multiple therapies may be effective for the individual, the genetic makeup of the HIV in the infected population will change and HIV will become resistant to any widely used therapy.
There are a number of other chronic persistent diseases caused by RNA or DNA viruses that replicate through an RNA intermediate which are equally difficult to treat. Among the candidate human viral diseases are hepatitis B and C, T-cell human leukemia as well as other diseases. Important RNA viral diseases of animals include feline leukemia and immunodeficiency, Visna maedi of sheep, bovine viral diarrhea, bovine mucosal disease, and bovine leukemia. Even though the viruses that are associated with these diseases are replicated by an RNA dependent DNA polymerase, the RNA genomes are synthesized by the mammalian RNA polymerase.
Hepatitis B is caused by a DNA virus that replicates its genome through an RNA intermediate (Summers and Mason, Cell 29:4003 (1982). While an effective vaccine exists as a preventive there is no efficacious treatment for chronic persistent infection. Currently, it is estimated that 50 million individuals who harbor the virus are carriers and are chronically infected. Chronic infection with hepatitis B is associated with a 217-fold increase in primary hepatoma and invariably fatal cancer (Beasley and Hwang, Seminars in Liver Disease 4:113 (1984). Hairy cell leukemia is associated with HTLV-1 infection and is prevalent in Japan (Ehrlich, et al., Virology 186:619 (1992). The association of an RNA tumor virus with this human cancer could be predictive of a relation of RNA viruses with other human cancers but this remains to be established.
Finally, a number of common human diseases are caused by RNA viruses that are replicated by a viral encoded RNA replicase. Included in this group are influenza (Zurcher, et al., J. Gen. Virol. 77:1745 (1996), hepatitis C (Gretch, et al., Ann. Intern. Med. 123:321 (1995), dengue fever (Becker, Virus-Genes 9:33 (1994), and rhinovirus infections (Horsnell, et al., J. Gen. Virol., 76:2549 (1995). Replication of these viruses by the viral RNA replicase is error prone and thus these viruses are likely to evolve rapidly and evade conventional drug or immunotherapies. Currently there is no effective therapy for these diseases. While vaccination against influenza can be effective, a new vaccine must be generated each year depending on the mutations that were fixed in the circulating strain in the previous year, a consequence of the rapid evolution of the viral genome. Current treatment of hepatitis C employs interferon, but it is seldom curative for the disease.
Thus, there exists a need for an effective prevention or amelioration of RNA virus mediated diseases. The present invention satisfies this need and provides related advantages as well.